The ubiquitous distribution of sex steroid receptors throughout the brain suggests that gonadal hormones are important modulators of cognitive function. Endocrine abnormalities in the hypothalamic-pituitary-gonadal axis have been documented in injection drug users (IDU) and are likely due to a combination of direct drug effects and associated co-morbidities. Our overall hypothesis is that there is cognitive dysfunction in IDU due to CNS alterations secondary to hypogonadism associated with IDU, and that poor performance on standardized cognitive tests can be improved by administering sex steroid replacement. To test our hypothesis we propose the following specific aims: (#1) To document the gonadal hormonal milieu in a population of IDU, and to understand the relationship of that milieu to cognitive performance and quality of life (QOL). (#2) To characterize patterns of cognitive performance and QOL in a defined population based on IDU and HlV status using standardized cognitive testing. (#3) To evaluate the safety and efficacy of sex hormone replacement therapy (either testosterone in men or estrogen in women) on cognitive performance and QOL in a subgroup of hypogonadal IDU. We propose two studies: a cross-sectional study of IDU to evaluate patterns of cognitive performance in relation to their gonadal hormone milieu and, a randomized, placebo-controlled, clinical trial in which hypogonadal IDU will be administered sex hormone replacement to determine the effects on cognitive performance and QOL. We have assembled a multidisciplinary team with extensive experience in studying IDU populations, endocrine abnormalities, and performance on cognitive tasks influenced by sex steroids. We will obtain a better understanding of the relationship between drug use and cognition, and also expand our understanding of the effects of sex steroids on cognitive performance, in an under-studied population.